title: Role of IRF4 in IFN-stimulated gene induction and maintenance of Kaposi sarcoma-associated herpesvirus latency in primary effusion lymphoma cells.
abstract: IFN regulatory factor (IRF) 4 is a hematopoietic cell-specific transcription factor that regulates the maturation and differentiation of immune cells. Using an inducible expression system, we found that IRF4 directly induced a specific subset of IFN-stimulated genes (ISGs) in a type I IFN-independent manner in both epithelial and B cell lines. Moreover, Kaposi sarcoma-associated herpesvirus (KSHV)-encoded viral FLICE inhibitory protein (vFLIP) enhances IRF4-mediated gene induction. Coexpression of IRF4 with vFLIP significantly increased ISG60 (IFIT3) and Cig5 (RSAD2) transcription that was dependent on the ability of vFLIP to activate NF-κB. A vFLIP mutant (A57L) defective in NF-κB activation failed to enhance IRF4-mediated ISG induction. Thus, we provide a physiologically relevant mechanism by which viral protein-mediated NF-κB activation modulates specific ISG induction by IRF4. In contrast, IRF4 also acted as a negative regulator of KSHV replication and transcription activator expression after induction of KSHV lytic reactivation in KSHV-positive primary effusion lymphoma cells. Taken together, these results suggest a dual role for IRF4 in regulating ISG induction and KSHV lytic reactivation in primary effusion lymphoma cells.
authors.affiliation: Cancer Virology Program, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Adriana
authors.initials: A
authors.lastname: Forero
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Moore
authors.forename: Saumendra N
authors.initials: SN
authors.lastname: Sarkar
mesh_terms: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D004789:Enzyme Activation / Q000235:genetics; D015870:Gene Expression; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D007370:Interferon Type I; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008223:Lymphoma / Q000235:genetics / Q000821:virology; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011506:Proteins / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics; D015533:Transcriptional Activation; D017735:Virus Latency; D014779:Virus Replication / Q000235:genetics; D000099218:Interferon Regulatory Factor-4; D000090123:Viperin Protein
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D050835:Interferon Regulatory Factors; D007370:Interferon Type I; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011506:Proteins; D000099218:Interferon Regulatory Factor-4; C116468:IFIT3 protein, human; C444427:RSAD2 protein, human; D000090123:Viperin Protein